Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Ito M. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res 2007;30:1029-34.

            187 men had measurement of flow-mediated vasodilation as a measurement of endothelial function and NO release. It was significantly correlated with total and free testosterone independent of age, BMI, hypertension, hyperlipidemia, and smoking (p< 0.01). This finding is consistent with the effect of castration on erectile function (Traish 2003) and T therapy on increasing penile NO (Garban).

Akkus E, Kadioglu A, Esen A, Doran S, Ergen A, Anafarta K, et al. Prevalence and Correlates of Erectile Dysfunction in Turkey: A Population-Based Study. European Urology 2002;41:298-304.

            This large population study examined the factors related to ED in men over age 40. ED was decreased by two-thirds in moderately active men and by over 80% in active men. Use of alcohol was associated with almost a 60% reduction of ED. The total incidence of mild, moderate, and severe ED was 70%, which may have been higher because physicians did all of the interviews.

Aydinoglu F, Yilmaz SN, Coskun B, Daqlioglu N. Oqulener N. Effects of ethanol treatment on the neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle in the mouse. Pharmacol Rep 2008;60:725-34.

            This study of the corpus cavernosum of the mouse found that alcohol reduced endothelial NO release, but neural NO release remained intact.

Aytac IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50-6.

            Mild, moderate and severe ED is projected to affect over 600 million men by the year 2025. Assuming that questionnaires underestimate the incidence of ED (Akkus, above), probably close to a half billion men in the world currently have some degree of ED.

Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. Sexual function in men older than 50 years of age: results from the health professionals follow-up study. Ann Int Med 2003;139:161-8.

            In this study of health professionals, smoking was correlated with ED. Television viewing, as a surrogate for inactivity, was associated with more ED. In men with depression, a 70% increase in ED was observed.

Buga GM, Gold ME, Fukuto JM, Ignarro LJ. Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension 1991;17:187–93.

            This study was the first to show increased NO release due to the shear stress effect on endothelial cells. This appears to be triggered by calcium flux across the cell membrane.

Cayan S, Bozlu M, Canpolat B, Akbay E. The assessment of sexual functions in women with male partners complaining of erectile dysfunction: does treatment of male sexual dysfunction improve female partner's sexual functions? J Sex Medical Ther 2004;30:333-41.

            This study showed marked decreases in sexual function in female partners of men with ED and dramatic improvements with successful treatment of ED. It shows that ED is generally not secondary to female sexual dysfunction, and that the female responds very well to better erectile performance.

Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int 1999;83:269-73.

            This study showed that that 5 gm per day of L-arginine improved ED in men with reduced NO production.

Cheng C, van Haperen R, de Waard M, van Damme LCA, Tempel D, Hanemaaijer R, et al. Shear stress affects the intracellular distribution of eNOS: direct demonstration by a novel in vivo technique. Blood 2005;106:3691-8.

            This study elegantly demonstrated the marked induction of eNOS in endothelial cells by shear stress, using eNOS green fluorescent protein as a marker.

Chiurlia E, D'Amico R, Ratti C, et al. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol 2005;46:1503-6.

            Men with ED develop coronary artery calcification at a younger age than controls, leading these investigators to call ED “penile angina”

Derby CA, Mohr BA, Goldstein I, Feldman HA, Johannes CB, McKinlay JB. Modifiable risk factors and erectile dysfunction: can lifestyle changes modify risk? Urology 2000;56:302-6.

            ED was associated with obesity and baseline and initiated physical activity. ED remained associated with obesity after weight loss. Physical activity appears to be of greater importance than weight loss, but the two usually go together, making it difficult to say which is more important.

Deutsch S, Sherman L. Previously unrecognized diabetes mellitus in sexually impotent men. JAMA 1980;244:2430-2.

            Twelve percent of men with ED were found to have unrecognized diabetes. Health screening of blood sugar, blood pressure, and blood lipids will often turn up unrecognized health problems in these men.

Dulloo A, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, at al. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Amer J Clin Nutr 1999;70:1040-5.

            In this study green tea extract increased energy expenditure (EE) by 4%. Caffeine at the amount present in the extract had no effect. Fat oxidation was also increased, showing that fat was being utilized for thermogenesis. The increased EE observed, for an average adult would translate to 50 calories daily and 5 pounds of weight loss per year.

Eaton CB, Liu YL, Mittleman MA, Miner M, Glasser DB, Rimm EB. A retrospective study of the relationship of biomarkers of atherosclerosis and erectile dysfunction in 988 men. Int J Impot Res 2007;19:218-25.

            ED was associated with a reduced HDL/LDL ratio. Exercise, alcohol and a low fat diet will improve this ratio. Oxidation of LDL is a major contributor to atherosclerosis. Statins are very effective in lowering LDL cholesterol and thereby reducing cardiovascular disease.

Esposito K, Giugliano F, Di Palo C, Giugliano G, Marfella R, D’Andrea F, et al: Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled study. JAMA 2004;291:2978-84.

            ED was strongly associated with an increased waist/hip (W/H) ratio. ED was significantly improved with weight loss and increased activity. These interventions lowered glucose, insulin, W/H ratio, blood pressure, triglycerides, and increased endothelial NO release.

Esposito K, Ciotola M, Giugliano F, De Sio M, Giugliano G, D’Armiento M, et al. Mediterranean diet improves erectile function in subjects with the metabolic syndrome. Int J Impot Res 2006;18:405-10.

            In a randomized study, men with MetS who followed the Mediterranean diet had significant reductions of systolic blood pressure, LDL, triglycerides, CRP, glucose, and insulin, and significant increases of HDL, endothelial function and ED score. The intervention group significantly increased their intake of healthy oils, omega-3 fats, and vegetables/fruits/nuts/legumes. 37% of the treatment group achieved an ED score of greater than 22. These men with MetS and severe ED may not have had as poor a diet at baseline as that of the typical American, as this study took place in Italy. It does illustrate that a multifaceted approach is necessary to achieve a marked improvement of ED, particularly when it is severe.

Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massechusettes Male Aging Study. J Urol. 1994;151:54-61.

            This study found that the incidence of ED in men ages 40 to 70 was 52%. Questionnaires probably underestimate the incidence of this sensitive function. In another study the patients were interviewed by a physician and the incidence was 69% (Akkus).

Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med 2000;30:328-38.

            Smoking doubled the risk of ED in this study, and second-hand smoke also increased the risk. The risk estimates have not been as high in other studies on smoking and ED, but the relationship to ED might be one further factor that could convince a smoker to kick the habit.

Fisher ND, HughesM, Gerhard-Herman, Hollenberg NK. Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens 2003;21:2281-6.

            Cocoa ingested four times daily for 5 days increased vasodilation and this was blocked by L-NAME, an inhibitor of NO production. A further acute response was seen 90 minutes after a single dose on day 5. This study was in normal individuals, indicating that NO can be further stimulated in people without any overt signs of cardiovascular disease. The amounts of flavinols ingested would be equivalent to the amount of anti-oxidant recommended on this web site (lots of fruits and vegetables, 3 cups of green tea per day, 50-100 mg of pycnogenol, and 1 oz. of no sugar dark chocolate.

Fitzpatrick DF, Bing B, Rohdewald P. Endothelium-dependent vascular effects of Pycnogenol. J Cardiovasc Pharmacol 1998;32:509-15.

            Pycnogenol increases eNOS in vascular endothelium.

Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol 2004;43:1405-11.

            Coronary risk factors in mid-life predicted the later development of ED

Giugliano F, Esposito K, Di Palo C, Ciotola M, Giugliano G, Marfella R, et al: Erectile dysfunction associates with endothelial dysfunction and raised proinflamatory cytokines in obese men. J Endocrinol Invest 2004;27:665-9.
            The title says it all.

Goldstein I, Fisher WA, Sand M, Rosen RC, Mollen M, Brock G, et al. Women's sexual function improves when partners are administered vardenafil for erectile dysfunction: a prospective, randomized, double-blind, placebo-controlled trial. J Sex Med 2005;2:819-32.

            Treatment of ED markedly improved arousal, lubrication, orgasm, and sexual satisfaction in the female partner.

Goldstein I, Lue TF, Padma-Nathan H, Rosen, RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. New Engl J Med 1998;338:1397-404.

            Over 500 men with ED were treated with sildenafil (Viagra) or placebo. Although highly efficacious, treatment only allowed the men to achieve 4 fully rigid erections per month.

Gur S, Kadowitz PJ, Trost L, Hellstrom WJG. Optimizing nitric oxide production by time dependent L-Arginine administration in human corpus cavernosum. J Urol 2007;178:1543-8.

            L-arginine was found to potentiate the response of human corpus cavernosum tissue to sildenafil in vitro.

Hambrecht R, Adams V, Erbs S, Linke A, Krankel N, Shu Y, et al. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 2003; 107:3152–8.

            Diseased arteries also respond to exercise with increased NO production.  

Hamilton IM, Gilmore WS, Benzie IF, Mulholland CW, Strain JJ. Interactions between vitamins C and E in human subjects. Br J Nutr 2000;84:261-7.

            Ingestion of either Vitamin C or vitamin E leads to higher serum levels of the other vitamin. This observation may underlie the finding of synergism in other studies regarding the effect of these two vitamins on NO production.

Haram PM, Adams V, Kemi OJ, Brubakk AO, Hambrecht R, Ellingsen O, et al. Time-course of endothelial adaptation following acute and regular exercise. Eur J Cardiovasc Prev Rehabil 2006;13:585-91.

               A single episode of exercise increased vascular NO production for 48 hours, whereas regular daily exercise caused four-fold higher vascular NO production that lasted for about a week. We recommend moderate to vigorous activity every day for men with ED.

Hayashi T, Juliet PA, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J, et al. l-Citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci 2005;102:13681-6.

            Either L-arginine or L-citrulline increased NO production by blood vessels in rabbits on a high cholesterol diet. When both amino acids were given together with Vitamin C and vitamin E, atherosclerosis was dramatically lessened compared with controls.

Hecker M, Sessa WC, Hayley J, Harris J, Anggard EE, Vane JR. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: Cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci 1990;87:8612-6.
           
            L-citrulline is a byproduct of NO production and is recycled to L-arginine within the cell. Other studies have shown that intracellular L-arginine is the critical source of precursor for NOS.

Hong B, Ji YH, Hong JH, Nam KY, Ahn TY. A double-blind crossover study evaluating the efficacy of korean red ginseng in patients with erectile dysfunction: a preliminary report. J Urol 2002;168:2070-73.

            Ginseng was shown to benefit ED in a well designed study. However, ginseng comes from many sources, so there is no standardization of antioxidant potency among different products.

Ignarro LJ, Balertrieri ML, Napoli C. Nutrition, physical activity, and cardiovascular disease: An update. Cardiovasc Res 2007;73:326-40.

            A good review of this topic and well referenced.

Ignarro LJ, Byrns RE, Sumi D, de Nigris F, Napoli C. Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biologic actions of nitric oxide. Nitric Oxide 2006;15:93-102.         

            Pomegranate juice is a very potent antioxidant, and protects NO from oxidative destruction. However, Pomegranate juice is very bitter and therefore commercial products have added sugar. This may be why a controlled trial of Pomegranate juice versus placebo did not reach statistical significance in treating men with ED.
Jackson G, Rosen RC, Kloner RA, Kostis JB. The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med 2006;3:28-36.

            The correlation of ED with cardiovascular disease and risk factors is so strong that: “…a man with ED and no cardiac symptoms is a cardiac (or vascular) patient until proven otherwise.”

Jian L, Xie LP, Lee AH, Binns CW. Protective effect of green tea against prostate cancer: A case-control study in southeast China. Int J Cancer 2004;108:130-5.

            Prostate cancer is very uncommon in China. In this study the adjusted odds ratio for Chinese men drinking more than 3 cups daily was 0.27, and for consumption for more than 40 years the ratio was 0.12. In addition to its vascular benefits, green tea appears to be highly protective against development of prostate cancer.

Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process. Atherosclerosis (2009), doi:10.1016/j.atherosclerosis.2009.04.016

            This article in press is a very thorough review of the role of low testosterone levels in the aging male on the metabolic syndrome and atherosclerosis.

Kalea AZ, Clark K, Schuschke DA, Kimis-Zacas DJ. Vascular reactivity is affected by dietary consumption of wild blueberries in the Sprague-Dawley rat. J Med Food 2009 12:21-8.

            Blueberries were shown to increase vascular NO production. The health benefits of blueberries have been widely promoted, but in one study, strawberries had the same antioxidant content, and blackberries had twice the amount of antioxidant compared to blueberries.

Klotz T, Mathers MJ, Braun M, Bloch W, Engelmann U. Effectiveness of Oral L-Arginine in First-Line Treatment of Erectile Dysfunction in a Controlled Crossover Study. Urol Int 1999;63:220-3.

            At a dose of 1.5 gm daily, this well-designed study showed no benefit on ED. Only about one-third of oral L-arginine is absorbed intact. Other studies have shown that 5 gm has a beneficial effect on ED.

Koskimaki J, Rahman S, Tammela T, Hakkinen J, Hakama M, Auvinen A. Regular Intercourse Protects Against Erectile Dysfunction: Tampere Aging Male Urologic Study. Amer J Med 2008;121:592-6.

            These investigators found a two-fold increase of ED with less frequent coitus in men between ages 55 and 75. Use it or lose it!

Kupelian V, Shabsigh R, Araujo AB, O'Donnell AB, McKinlay JB. Erectile dysfunction as a predictor of the metabolic syndrome in aging men: results from the Massachusetts Male Aging Study. J Urol 2006;176:222-6.

            In this study ED was highly correlated with the metabolic syndrome.

LuggJ, Rajfer J, Gonzalez-Cadavid NF. Dihydrotestosterone is the active androgen in the maintenance of nitric-oxide-mediated penile erection in the rat. Endocrinology 1995;136:1495-501.

            Castration reduced the nerve-stimulated erectile response in the rat. Erectile response was restored by testosterone, and this effect was mediated by conversion of testosterone to dihydrotestosterone and by nitric oxide.

Meldrum DR, Gambone JC. Survival of the Firmest. Charleston, South Carolina: Booksurge, 2009.

            This book details the lifestyle factors that influence the chance of a man having ED and gives specific recommendations that are based on evidence of improved NO production or decreased ED.

Moens AL, Vrints CJ, Claeys MJ, Timmermans JP, Kass DA. Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease. Am J Physiol Heart Circ Physiol 2008;249:H1971-7.

            Folic acid is integrally involved in NO production. Dietary intake and supplements should assure the recommended daily allowance (RDA) of 400 micrograms.

Montorsi F, Briganti A, Salonia A, Rigatti P, Margonato A, Macchi A, et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003;44:360-4.

            In men with angiographically proven atherosclerotic heart disease, symptoms of Ed had begun an average of 39 months previously. This study showed that intervention must occur before the actual diagnosis of ED, as 39 months would be too short a time to expect that lifestyle interventions could prevent this extent of vascular disease.

Muniyappa R, Quon MJ. Insulin action and insulin resistance in vascular endothelium. Curr Opin Clin Nutr Metab Care 2007;10:523–530.

            This is an excellent review of the involvement of insulin and insulin resistance in vascular disease.

Okuda Y, Kawashima K, Sawada T,  Tsurumaru K, Asano M, Suzuki S, et al: Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells. Biochem Biophys Res Commun 1997;232:487-91.

            A very prompt and marked increase of NO production was observed when EPA, one of the two main omega-3 fatty acids, was exposed to human endothelial cells.

Persson IA, Josefsson M, Persson K, Andersson RG. Tea flavinols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells. J Pharm Pharmacol 2006;58:1139-44.

            Tea flavinols increase vascular NO production. , but also inhibit angiotensin-converting enzyme activity.

Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ: Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. New Engl J Med 1992;326:90-4.

            This landmark study showed that neural stimulation resulting in increased penile blood flow and erection is mediated by NO and in turn by the stimulation of cyclic GMP.
Roberts CK, Nosratola D, Vaziri MD, Barnard J. Effect of diet and exercise intervention on blood pressure, insulin, oxidative stress, and nitric oxide availability. Circulation 2002;106:2530-32.

            Obese men underwent a program of vigorous daily exercise. The decrease in circulating insulin, reflecting increased insulin sensitivity, correlated with increased NO production. The increased NO production could have been due to improved insulin action, as insulin stimulates NO, but it also could have been due to reduced circulating glucose.

Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther 2002;40:158-68.

            This is a good review of the pharmacology of pycnogenol. This procyanidin is a potent antioxidant in the general class of polyphenols also present in red wine, chocolate, blueberries and green tea. Procyanidins have 20 to 50 times the antioxidant content compared to vitamin C and vitamin E.

Rosen RC, Wing RR, Scneider S, Wadden TA, Foster GD, West DS, et al. Erectile dysfunction in type 2 diabetic men: relationship to exercise fitness and cardiovascular risk factors in the Look AHEAD trial. J Sex Med 2009;6:1414-22.

            In men with type 2 diabetes cardiovascular fitness was associated with 40% less ED.
Rosenthal BD, May NR, Metro MJ, Harkaway RC, Ginsberg PC. Adjunctive use of Androgel (testosterone gel) with sildenafil to treat erectile dysfunction in men with acquired androgen deficiency syndrome after failure using sildenafil alone. Urology 2006;67:571-4.

            In 24 men with hypogonadism who failed to have adequate erections with either sildenafil or testosterone therapy alone, 92% regained potency with the two agents combined.

Saldeen P, Saldeen T. Women and omega-3 fatty acids. Obstet Ginecol Surv 2004;59:722-30.

            This review refers to the evidence that increased dietary intake of omega-3 fatty acids shifts the balance away from vasoconstricting toward vasodilating prostaglandins. In this way, omega-3’s act similarly to penile injections or urethral suppositories of prostaglandin E1 that are prescribed by urologists when other less invasive treatments for ED fail.

Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol 2008;65:51-9.

            The circulating levels of L-arginine, the direct precursor of NO, are over twice as high after ingestion of L-citruline compared to ingestion of L-arginine. L-citrulline also acts within the cell as a precursor of L-arginine. Because 5 gm of L-arginine orally per day benefits ED, 2 gm of L-citrulline should have a similar effect.

Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US.  Am J Med 2007;120:151-7.

            The incidence of ED was found to be three-fold higher in diabetic men. Endothelial dysfunction is worse in men with diabetes because elevated circulating glucose inhibits NO production by inducing mitochondrial dysfunction with release of oxidation products that inactivate NO. High glucose levels also promote production of advanced glycation end-products (AGE’s), that accumulate with age and are potent oxidation products contributing to vascular oxidative stress. The high sugar intake of the current American diet would promote similar negative effects on NO release.

Shamloul R, Ghanem HM, Salem A, et al.  Correlation between penile duplex findings and stress electrocardiography in men with erectile dysfunction. Int J Impot Res 2004;16:235-7.

            These investigators found a correlation of penile systolic velocity and ischemic heart disease.

Shindel AW, Nelson CJ, Naughton CK, Ohebshalom M, Mulhall JP. Sexual function and quality of life in the male partner of infertile couples: prevalence and correlates of dysfunction. J Urol 2008;179:1056-9.

            The incidence of sexual disfunction was found to be 20-25% in infertile couples.

Stanislavov R, Nikolova V. Treatment of erectile dysfunction with pycnogenol and L-arginine. J Sex Marital Ther 2003;29:207-13.

            Men with ED showed no improvement on an ineffective dose of L-arginine (1.5 gm daily), but over a further two month period with addition of 80 to 100 mg of the procyanidin, pycnogenol, 93% had improved ED scores.

Stanislavov R, Nikalova V, Rohdewald P. Improvement of erectile function with Prelox: a randomized, placebo-controlled crossover trial. Int J Impotence Res 2008;20:173-80.

            This study showed a highly significant benefit of a four week treatment of 80 mg of pycnogenol and 3 gm of L-arginine daily. The use of two supplements makes it difficult to determine which contributed to the results. One must assume that each contributed to the effects observed.

Stanworth RD, Jones TH. Testosterone for the aging male: current evidence and recommended practice. Clin Interv Aging 2008;3:25-44.

            This is an excellent review of the correlation of low/low/normal testosterone levels with central obesity, insulin resistance, cardiovascular risk factors, and other adverse changes such as cognition, and the evidence that a proper level of testosterone treatment can improve these adverse effects, including diabetes control and may reduce the risk of Alzheimer’s.

Tagliabue M, Pinach S, Di Bisceglie C, Brocato L, Cassader M, Bertagna A, et al. Glutathione levels in patients with erectile dysfunction, with or without diabetes mellitus. Int J Androl 2005;28:156-162.

            Levels of red cell reduced glutathione (GSH) were lower in men with ED. The very narrow standard errors of GSH levels indicated this is a consistent finding in these men, most likely reflecting reduced intake of antioxidants.

Tomasian D, Keaney JF, Vita JA. Antioxidants and the bioactivity of endothelium-derived nitric oxide. Cardiovasc Res 2000;47:426-435.

            This is a good review of the actions of vitamins C and E on vascular NO production. These two vitamins may play specific roles in NO production.

Traish AM, Munarriz R, Oconnell L, Choi S , Kim SW, Kimm NM, et al. Effects of medical or surgical castration in an animal model. J Androl 2003;24:381-7.

            Castration led to a reduced intracavernosal blood pressure, but NOS activity was unchanged. There was decreased smooth muscle content of erectile tissue. This finding, and the finding that testosterone replacement prevents effects of castration on erectile function suggest that part of the effect of androgen deficiency is via changes over time of cavernosal smooth muscle content.

Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009;30:10-22.

            This is a very thorough review of the strong relationship of the metabolic syndrome (MetS) and both low testosterone levels and erectile dysfunction.  Also cited is evidence that testosterone therapy improves both ED and some aspects of MetS. The authors propose that T deficiency contributes to MetS and that MetS contributes to lower T levels. In men with low T levels, T replacement improves ED as well as MetS.

van Mierlo LAJ, Arends LR, Streppel MT, Zeegers MPA, Kok FJ, Grobbee DE, et al. Blood pressure response to calcium supplementation: a meta-analysis of randomized controlled trials. J Hum Hypertens 2006;20:571-80.

            Meta-analysis of randomized trials showed a small but significant effect of calcium supplementation on blood pressure. Multiple points in the synthesis of NO are calcium dependent. In men with deficient calcium intake, increasing dietary calcium or taking supplements may aid NO synthesis.

Wallerath T, Poleo D, Li H, Forstermann U. Red wine increases the expression of human endothelial nitric oxide synthase: a mechanism that may contribute to its beneficial cardiovascular effects. J Am Coll Cardiol 2003;41:471-8.

            The polyphenols in red wine are probably responsible for the French paradox and the increased longevity of people living in the southwestern part of France and Sardinia. Resveratrol is probably less important due to its lower concentration in wine than other polyphenols and because of its reduced bioavailability. Interestingly, the benefits of red wine are inconsistent. In one study German red wine did not produce the same vascular effect as French wine, and some regions of France produce wine with higher a content of polyphenols.

White JR, Case DA, McWhirter D, Mattison AM. Enhanced sexual behavior in exercising men. Arch Sex Behav 1990;19:193-209.

            In normal men, exercise led to increased sexual behavior.

Woodman CR, Muller, JM, Laughlin MH, Price, EM. Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs. Am J Physiol 1997;273:H2575-9.
            Exercise training increased eNOS mRNA in coronary arteries.

Yang AL, Su CT, Lin KL, Chao JI, You HP, Lee SD. Exercise training improves insulin-induced and insulin-like growth factor-1-induced vasorelaxation in rat aortas. Life Sci 2006;79:2017-21.

            Exercise increased the sensitivity of NO production in response to insulin, manifested by increased eNOS expression and activity.

Zorgniotti AW, Lizza EF. Effect of large doses of the nitric oxide precursor, l-arginine, on erectile dysfunction. Int J Impot Res 1994;6:33-35.
            In men with mild ED, a well-designed study showed a benefit with 5 gm daily of L-arginine.